Genetic regulation of indoleamine-2,3-dioxygenase and psychiatric complications of IFN-alpha therapy Psychiatric complications are the often side effects of interferon-alpha (IFN-alpha) therapy of hepatitis C. Literature suggests that the up-regulation of indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway of tryptophan (TRY) metabolism, is responsible for the depression, anxiety, and psychosis observed during IFN-alpha therapy: a) activation of IDO shunts TRY metabolism to increased production of kynurenines, and away from synthesis of serotonin, the major substrate of antidepressant action;and b) kynurenine metabolites have anxiogenic and psychotomimetic effects. IDO is transcriptionally induced by pro-inflammatory cytokines. IFN-alpha stimulates IDO activity and production of IFN-gamma (IFNG) (the strongest transcriptional inducer of IDO), and of tumor necrosis factor-alpha (TNF-alpha) that amplifies IFNG-induced IDO expression. IFNG (+874) (T/A) and TNF-alpha(-308) (A/G) genotypes might predetermine the level of IFNG and TNF-alpha production, and, consequently, the degree of IDO activity and the frequency of psychiatric complications associated with IFN-alpha treatment. We suggest that combination of the high promoter T of IFNG (+874) with the high promoter A of TNF-alpha (-308) alleles might result in "super-induction" of IDO, and, therefore, in increased risk of psychiatric complications in IFN-alpha treated patients. Our working hypothesis is that individuals possessing a combination of high promoter alleles of IFNG (TT+TA) and TNF-alpha (AA+AG) are more prevalent among IFN-alpha treated patients with psychiatric complications than in patients without psychiatric complications. We propose a cross-sectional retrospective study of IFNG (+874)(T/A) and TNF-alpha(-308) (A/G/) gene polymorphisms in hepatitis C patients with and without psychiatric complications in response to IFN-alpha treatment. The obtained data might justify further studies of association between genotypes, cytokines levels, IDO activity and psychiatric complications, and suggest new ways of prediction and treatment of psychiatric complications of IFN-alpha therapy of hepatitis C and other IFN-alpha treated conditions, e.g., cancer, amyotrophic lateral sclerosis and multiple sclerosis. PUBLIC HEALTH RELEVANCE: The proposed study aims to investigate whether analysis of cytokine gene polymorphisms might help to identify hepatitis C patients with high risk of developing psychiatric complications in response to IFN-alpha therapy